Causal Sensitivity Analysis for Hidden Confounding: Modeling the Sex-Specific Role of Diet on the Aging Brain

Abstract

Modifiable lifestyle factors, including diet, can impact brain structure and influence dementia risk, but the extent to which diet may impact brain health for an individual is not clear. Clinical trials allow for the modification of a single variable at a time, but these may not generalize to populations due to uncaptured confounding effects. Large scale epidemiological studies can be leveraged to robustly model associations that can be specifically targeted in smaller clinical trials, while modeling confounds. Causal sensitivity analysis can be used to infer causal relationships between diet and brain structure. Here, we use a novel causal modeling approach that is robust to hidden confounding to partially identify sex-specific dose responses of diet treatment on brain structure using data from 42,032 UK Biobank participants. We find that the effects of diet on brain structure are more widespread and also robust to hidden confounds in males compared to females. Specific dietary components, including a higher consumption of whole grains, vegetables, dairy, and vegetable oils as well as a lower consumption of meat appears to be more beneficial to brain structure (e.g., greater thickness) in males. Our results shed light on sex-specific influences of hidden confounding that may be necessary to consider when tailoring effective and personalized treatment approaches to combat accelerated brain aging.

E. Haddad and M.G. Marmarelis—These authors contributed equally to this work.